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Therapy for Fungal Diseases: Opportunities and Priorities

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Therapy for Fungal Diseases: Opportunities and Priorities TIMI-711; No. of Pages 10 Review Therapy for fungal diseases: opportunities and priorities David W. Denning and William W. Hope School of Translational Medicine, Manchester Academic Health Science Centre, University of Manchester, University Hospital of South Manchester, Manchester M23 9LT, UK This article provides a perspective on the current status Currently, five classes of antifungal agents are used of drug therapy for invasive fungal diseases, together orally or intravenously for the treatment of fungal infections with priorities for the future development of novel com- in humans: polyenes, pyrimidine analogues, allylamines, pounds. Key opportunities for new drugs include pro- azoles and the echinocandins (Table 1). Each antifungal duction of orally bioavailable agents for the treatment of compound has advantages and limitations related to its invasive aspergillosis, invasive candidiasis, cryptococcal spectrum of activity (Table 2), route of administration, drug meningitis and mucosal and urinary Candida infections. interactions and toxicity profile. This review will describe Orally bioavailable agents for the treatment of chronic the role and limitations of these agents for the treatment of pulmonary and allergic aspergillosis are also required, as the most common and medically important syndromes. well as new potent drugs against a range of medically Agents that are in early phases of development will not important moulds. Antifungal resistance is a problem in be discussed. We reflect on the challenges and opportunities certain contexts, but is generally less of a problem than for the development of novel therapeutic strategies for the bacterial infections. Earlier and more complete myco- most common fungal syndromes as a way of improving logical diagnosis and improvements in underlying risk outcomes. Our key insights for drug development and future estimation will improve outcomes. The limitations of the research are summarised in Box 1 and Box 2. current antifungal agents and opportunities for new developments are discussed. Antifungal compounds Polyenes Fungal infections: the challenges ahead The polyenes are broad-spectrum antifungal agents pro- Invasive fungal infections are an increasing threat to duced by the bacterial genus Streptomyces. Nystatin was human health. In the developed world, these infections discovered in 1950 from the fermentation broth of Strep- predominantly occur in the context of increasingly tomyces noursei, and is still used as a topical antifungal aggressive immunosuppressive therapies. The overall agent. This was followed by isolation of fracidin, rimocidin, mortality for invasive diseases caused by Candida spp. endomycin, ascosin, trichomycin and antimycoin in the and Aspergillus spp. is 30–50%, despite the advent of early 1950 s [5]. Amphotericin A and B were isolated from new diagnostic and therapeutic strategies. In the devel- S. nodosum and reported in 1955 [6], but only amphoter- oping world, there are 1 million cases of cryptococcal icin B was developed because of its superior potency. Since disease per year, resulting in 675 000 deaths [1]. Allergic then, 90 polyenes have been discovered, but problems fungal syndromes are increasingly recognised [2].Con- with solubility, stability, oral bioavailability and toxicity tinued efforts are required to improve the often subopti- have prevented many of these compounds being developed mal therapeutic outcomes associated with fungal for clinical purposes [5]. Natamycin is still widely used as a infections. topical ophthalmic agent. The high degree of phylogenetic relatedness between The complex chemistry and systemic toxicity of the poly- fungi and humans means that there are relatively few enes provided the impetus to develop novel drug delivery differential targets to be exploited for antifungal drug systems that enable systemic therapy [7]. The best example development. Fungi are involved in an interminable of this is the lipid formulations of amphotericin B, although a struggle for survival with each other and with other liposomal formulation of nystatin was also developed [8]. microbes. They produce a vast array of extracellular The current commercially available lipid preparations of enzymes and secondary metabolites to counteract and amphotericin B include amphotericin B lipid complex digest the external world. Many antimicrobial agents have (ABLC), amphotericin B colloidal dispersion (ABCD) and been isolated from fungi themselves [3]. The best example liposomal amphotericin B (Figure 1). Other formulations are is penicillin, which was isolated from Penicillium notatum in various stages of clinical development, including prep- (now Penicillium chrysogenum) by Fleming, and later pur- arations that are orally bioavailable [9]. Lipid formulations ified for medical use by Florey and Chain [4]. Similarly, the differ significantly in terms of their pharmacokinetics, tissue echinocandins, a novel class of antifungal compounds now distribution and toxicity profile [10,11].AmphotericinB in widespread clinical use, are semisynthetic derivatives of formulations are widely used for the treatment of dissemi- fungal-derived cyclic hexapeptides. nated candidiasis, invasive aspergillosis, cryptococcal Corresponding author: Denning, D.W. ([email protected]). meningitis, and infections caused by the Mucorales [12,13]. 0966-842X/$ – see front matter ß 2010 Published by Elsevier Ltd. doi:10.1016/j.tim.2010.02.004 Available online xxxxxx 1 TIMI-711; No. of Pages 10 Review Trends in Microbiology Vol.xxx No.x Table 1. Characteristics of antifungal agents used to treat invasive or allergic diseasea Agent Routes of Frequency of Adverse events, Clinically relevant Comments administration administration toxicity drug–drug interactions Polyenes Amphotericin Ba IV, Nebulised Once daily Infusional toxicity, Renal impairment Lipid formulations associated with less nephrotoxicity, indirectly affects infusional toxicity and low blood potassium action of many nephrotoxicity drugs Pyrimidine analogues Flucytosine po, IV 1–4 times daily Bone marrow None Used for induction therapy for depending on suppression, cryptococcal meningitis; only renal function deranged LFT results in combination with another and blood levels antifungal agent; TDM necessary Azoles Fluconazole IV, po Once daily Gastrointestinal Few Some resistance, narrow intolerance, spectrum deranged LFT results Itraconazole po, IV Twice daily Fluid retention, Numerous, due to Oral bioavailability depends left ventricular inhibition of CYP 3A4b on specific formulation, dysfunction, with variability between gastrointestinal generic preparations; intolerance TDM ideally required Voriconazole IV, po, ocular Twice daily Deranged LFT Numerous, due to Nonlinear pharmacokinetics results, inhibition of CYP3A4c; and substantial inter-individual photosensitive some interactions with variability in serum concentrations; rash, altered CYP 2C19 metabolism very rapid metabolism in children; vision, hallucinations, (e.g. omeprazole) TDM ideally required confusion Posaconazole po 2–4 times daily Gastrointestinal Some, due to Other formulations in development; intolerance, inhibition TDM ideally required deranged LFT results of CYP3A4c Allylamines Terbinafine po Once daily Deranged LFT results, Few Used for fungal nail infections. mild rash, nausea, Not of use for invasive infection loss of taste Echinocandins Caspofungin IV Once daily Phlebitis, nausea, Ciclosporin, Modest efficacy as first-line agent deranged LFT results rifampicin for invasive aspergillosis (?in combination with other drugs) Micafungin IV Once daily Phlebitis, nausea, Few Modest efficacy as first line agent deranged LFT results for invasive and chronic aspergillosis Anidulafungin IV Once daily Histamine-like Few No data reported for aspergillosis reactions, diarrhoea, deranged LFT results Abbreviations: CYP 3A4, Cytochrome P450 isozyme 3A4; IV, intravenous; LFT, liver function test; po, oral; TDM, therapeutic drug monitoring. aAmphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex or amphotericin B colloid dispersion. bThe compound inhibits CYP 3A4 and leads to higher concentrations of drugs metabolised by this enzyme; low concentrations with compounds that accelerate metabolism through CYP 3A4 (e.g. rifampicin, anticonvulsants). Pyrimidine analogues interfere with DNA and RNA synthesis. [16]. The differ- Flucytosine (5-fluorocytosine; 5FC) was discovered in 1964 ential antifungal activity of flucytosine results from the by Roche Laboratories within an anti-neoplastic drug de- absence of cytosine deaminase in humans (Figure 2). velopment programme. Flucytosine does not have any In vitro studies described the emergence of resistance to intrinsic anti-neoplastic activity, but is active against flucytosine with concentrations < 25 mg LÀ1 [17], leading medically important yeasts such as Candida spp. and to the longstanding dogma that flucytosine should always Cryptococcus spp., and against a limited number of moulds be used in combination. Flucytosine causes bone marrow such as Aspergillus spp. and agents of chromoblastomyco- suppression, especially with peak plasma concentrations sis [14,15]. that are persistently >100 mg LÀ1, which is the primary Flucytosine is a pyrimidine analogue, which acts as a reason why therapeutic drug monitoring is essential [18]. subversive substrate within the pyrimidine salvage path- Flucytosine (in combination with another antifungal way that is responsible for scavenging precursors for agent) is the
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